CN109884301B - Biomarker for survival prognosis prediction of muscle-layer invasive bladder cancer and application of biomarker - Google Patents
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Abstract
Description
技术领域technical field
本发明属于及生物医药技术领域，尤其涉及一种用于肌层浸润性膀胱癌生存预后预测的生物标记物及其应用。The invention belongs to the technical field of biomedicine, and in particular relates to a biomarker for predicting survival and prognosis of muscle-invasive bladder cancer and its application.
背景技术Background technique
膀胱癌是泌尿系统最常见的恶性肿瘤。肌层浸润性膀胱癌指膀胱癌肿瘤突破基底层，侵袭至肌层，恶性程度高，预后差，5年总体生存率低。目前缺少简单有效的判断预后的生物标志物。转录组学的应用极大促进了对该疾病的分子特征及其与临床表现相关性的理解。但该方法依赖于转录数据，检测分析手段复杂，成本高，临床实施难度大。Bladder cancer is the most common malignant tumor of the urinary system. Muscle-invasive bladder cancer refers to bladder cancer tumors breaking through the basal layer and invading into the muscle layer, with a high degree of malignancy, poor prognosis, and a low 5-year overall survival rate. Currently, there is a lack of simple and effective biomarkers for judging prognosis. The application of transcriptomics has greatly advanced the understanding of the molecular characteristics of the disease and its correlation with clinical manifestations. However, this method relies on transcriptional data, and the detection and analysis methods are complex, costly, and difficult to implement clinically.
PPARG，即过氧化物酶体增生激活受体γ(peroxisome proliferative-activatedreceptor，gamma)，属核受体过氧化物酶体增生激活受体亚家族。PPARG在脂质合成、糖代谢、炎症反应、及动脉粥样硬化等生物过程中扮演重要角色，近期也证实其与多种肿瘤相关。在膀胱癌中，已有研究表明PPARG是一个潜在的治疗靶点，PPARG激动剂具有抑癌效果。PPARG, namely peroxisome proliferative-activated receptor γ (peroxisome proliferative-activated receptor, gamma), belongs to the nuclear receptor peroxisome proliferative-activated receptor subfamily. PPARG plays an important role in biological processes such as lipid synthesis, glucose metabolism, inflammatory response, and atherosclerosis, and has recently been confirmed to be associated with various tumors. In bladder cancer, studies have shown that PPARG is a potential therapeutic target, and PPARG agonists have tumor suppressor effects.
PDGFC，即血小板源性生长因子C(Platelet Derived Growth Factor C)，属于血小板源性生长因子家族。PDGFC在胚胎发育、血管生成、细胞增殖、细胞增殖分化、细胞迁移等过程中起重要的调控作用，近期研究发现其在肿瘤细胞生长及与肿瘤微环境的互作中扮演重要角色。PDGFC, Platelet Derived Growth Factor C (Platelet Derived Growth Factor C), belongs to the platelet-derived growth factor family. PDGFC plays an important regulatory role in embryonic development, angiogenesis, cell proliferation, cell proliferation and differentiation, and cell migration. Recent studies have found that it plays an important role in tumor cell growth and the interaction with the tumor microenvironment.
GAS6，即生长停滞特异性基因产物6(Growth Arrest Specific 6)，是酪氨酸激酶受体Axl、Ty-ro3和Mer配体，可刺激细胞增殖、细胞黏附和细胞迁移。GAS6/AXL信号转导在多种生物过程中扮演重要角色。GAS6在许多癌症中呈现高表达，参与肿瘤发展。GAS6, Growth Arrest Specific 6 (Growth Arrest Specific 6), is a ligand for tyrosine kinase receptors Axl, Ty-ro3 and Mer, which can stimulate cell proliferation, cell adhesion and cell migration. GAS6/AXL signal transduction plays an important role in a variety of biological processes. GAS6 is highly expressed in many cancers and is involved in tumor development.
DDR2，即盘状结构域受体2(Discoidin Domain Receptor 2)，在细胞与胞外微环境交互过程中起重要作用，受胞外基质成分调控，是一种与肿瘤发展进程密切相关的受体酪氨酸激酶，参与肿瘤的增殖、侵袭和转移等过程。其过表达在尿路上皮癌中发现与不良预后相关。DDR2, Discoidin Domain Receptor 2, plays an important role in the interaction between cells and the extracellular microenvironment, is regulated by extracellular matrix components, and is a receptor closely related to tumor development Tyrosine kinase, involved in the process of tumor proliferation, invasion and metastasis. Its overexpression was found to correlate with poor prognosis in urothelial carcinoma.
PDGFRA，即血小板源性生长因子受体α(platelet-derived growth factorreceptor alpha)，是血小板源性生长因子的细胞表面酪氨酸激酶受体。研究表明PDGFRA在器官发育、伤口愈合、和肿瘤进展过程中起重要作用。胃肠道间质瘤中常见突变激活，但在膀胱癌中扮演的角色未知。PDGFRA, platelet-derived growth factor receptor alpha (platelet-derived growth factor receptor alpha), is a cell surface tyrosine kinase receptor for platelet-derived growth factor. Studies have shown that PDGFRA plays an important role in organ development, wound healing, and tumor progression. Activating mutations are common in gastrointestinal stromal tumors but their role in bladder cancer is unknown.
FN1，即纤维连接蛋白1(Fibronectin 1)，是一种高分子糖蛋白，是细胞外基质的重要成份，参与细胞黏附和迁移等生物过程，在癌症中参与肿瘤的转移。在膀胱癌中，有研究报道FN1在癌症组织中高表达。FN1, or
这些生物标志物均可能为潜在的膀胱癌肿瘤标志物，但它们对预后的判断作用未知。These biomarkers may be potential bladder cancer tumor markers, but their role in judging prognosis is unknown.
发明内容Contents of the invention
为了于克服现有技术中的缺陷，本发明提供一种用于肌层浸润性膀胱癌诊断和/或生存预后预测的生物标记物及其应用，该生物标记物在肿瘤组织中的表达特征均具有预测肌层浸润性膀胱癌生存预后的价值。In order to overcome the defects in the prior art, the present invention provides a biomarker for the diagnosis and/or prediction of survival and prognosis of muscle-invasive bladder cancer and its application. The expression characteristics of the biomarker in tumor tissues are all It has the value of predicting the survival and prognosis of muscle invasive bladder cancer.
为实现上述目的，本发明采用如下技术方案：To achieve the above object, the present invention adopts the following technical solutions:
本发明的第一方面是提供一种用于肌层浸润性膀胱癌诊断和/或生存预后预测的生物标记物，其特征在于，所述生物标记物选自GAS6、PDGFC、DDR2、PDGFRA、FN1、PPARG中的至少一种。The first aspect of the present invention is to provide a biomarker for the diagnosis and/or survival prognosis prediction of muscle invasive bladder cancer, characterized in that the biomarker is selected from GAS6, PDGFC, DDR2, PDGFRA, FN1 , at least one of PPARG.
进一步地，所述生物标记物为双基因生物标记物，其选自GAS6/PPARG、PDGFC/PPARG、DDR2/PPARG、PDGFRA/PPARG和FN1/PPARG中的至少一种。Further, the biomarker is a dual gene biomarker, which is selected from at least one of GAS6/PPARG, PDGFC/PPARG, DDR2/PPARG, PDGFRA/PPARG and FN1/PPARG.
进一步地，所述生物标记物为双基因生物标记物，其为GAS6/PPARG、PDGFC/PPARG、DDR2/PPARG、PDGFRA/PPARG或FN1/PPARG。Further, the biomarker is a double-gene biomarker, which is GAS6/PPARG, PDGFC/PPARG, DDR2/PPARG, PDGFRA/PPARG or FN1/PPARG.
本发明的第二方面是提供一种上述生物标记物作为肌层浸润性膀胱癌诊断标志物和/生存预后预测标记物中的应用。The second aspect of the present invention is to provide an application of the above biomarker as a diagnostic marker and/or a predictive marker for survival and prognosis of muscle-invasive bladder cancer.
为了进一步优化上述应用，本发明采取的技术措施包括：In order to further optimize the above-mentioned application, the technical measures taken by the present invention include:
进一步地，所述GAS6、PDGFC、DDR2、PDGFRA和FN1在肌层浸润性膀胱癌肿瘤中的表达与PPARG的表达比值可分别作为独立的预后指标。Further, the ratio of the expression of GAS6, PDGFC, DDR2, PDGFRA and FN1 in muscle-invasive bladder cancer to the expression of PPARG can be used as independent prognostic indicators.
进一步地，所述生物标记物的表达比值的计算步骤包括：Further, the calculation steps of the expression ratio of the biomarkers include:
步骤一、处理标本以获得基因的定量数据；该步骤为检测肿瘤组织标本中双基因生物标记物的表达状况，其检测方法不限于上述定量数据的检测，上述检测方法均为本领域的常规检测方法，均遵循试剂盒给定的标准操作流程。
步骤二、根据所获得的定量数据，计算双基因生物标记物的表达比值，所述双基因生物标记物为GAS6/PPARG、PDGFC/PPARG、DDR2/PPARG、PDGFRA/PPARG或FN1/PPARG。Step 2. Calculate the expression ratio of the dual-gene biomarker based on the obtained quantitative data, and the dual-gene biomarker is GAS6/PPARG, PDGFC/PPARG, DDR2/PPARG, PDGFRA/PPARG or FN1/PPARG.
进一步地，所述步骤一具体为：标本采用RNA-Seq、RT-qPCR或转录组芯片获得RNA水平的基因转录定量数据，或标本通过免疫组化获得蛋白定量数据。Further, the first step specifically includes: using RNA-Seq, RT-qPCR or transcriptome chip to obtain quantitative data of gene transcription at the RNA level, or obtaining quantitative data of protein by immunohistochemistry.
进一步地，在所述步骤一中，所述标本为新鲜组织标本或甲醛固定石蜡包埋标本。Further, in the first step, the specimen is a fresh tissue specimen or a formaldehyde-fixed paraffin-embedded specimen.
进一步地，在所述步骤一中，每一双基因生物标记物中的两种标志物的定量数据必须使用同一种方法测定。Further, in the first step, the quantitative data of the two markers in each double-gene biomarker must be determined by the same method.
进一步地，标本中GAS6、PDGFC、DDR2、PDGFRA、FN1的表达均与PPARG的表达均呈负相关，较低比值对应的总体生存较好，不良预后风险低。Furthermore, the expressions of GAS6, PDGFC, DDR2, PDGFRA, and FN1 in the specimens were all negatively correlated with the expression of PPARG, and the lower ratios corresponded to better overall survival and lower risk of poor prognosis.
与现有技术相比，本发明采用上述技术方案具有以下有益效果：Compared with the prior art, the present invention adopts the above-mentioned technical solution and has the following beneficial effects:
本发明采用双基因分子特征用于判断肌层浸润性膀胱癌预后，其仅采用两种标志物，方法简单，容易实施；且采用的指标为两种标志物的表达比值，样本间可直接比较，无需进行样本间标准化处理。尤其针对组学数据可排除因标准化方法不同带来的影响。与采用转录组学分型和基因集特征谱的方法相比更加简单可行。The present invention adopts double-gene molecular characteristics to judge the prognosis of muscle-invasive bladder cancer. It only uses two markers, and the method is simple and easy to implement; and the index used is the expression ratio of the two markers, which can be directly compared between samples , without inter-sample normalization. Especially for omics data, the influence caused by different standardization methods can be excluded. Compared with methods using transcriptomic typing and gene set profiling, it is simpler and more feasible.
附图说明Description of drawings
图1为本发明一实施例中基于RNA-Seq数据的GAS6、PDGFC、DDR2、PDGFRA、FN1和PPARG基因的mRNA水平相关性分析结果图。Fig. 1 is a graph showing correlation analysis results of mRNA levels of GAS6, PDGFC, DDR2, PDGFRA, FN1 and PPARG genes based on RNA-Seq data in an embodiment of the present invention.
图2为本发明一实施例中各组双基因标志物按比值的总体生存分析结果图；其中，L：低比值组；M：中比值组；H：高比值组。Fig. 2 is a diagram of overall survival analysis results of digene markers in each group according to the ratio in an embodiment of the present invention; wherein, L: low ratio group; M: middle ratio group; H: high ratio group.
图3为本发明一实施例中各组双基因标志物按比值纳入分期和年龄因素进行Cox回归分析结果图；其中，L：低比值组；M：中比值组；H：高比值组。Fig. 3 is a Cox regression analysis result graph of the digene markers of each group in an embodiment of the present invention according to the ratio into the stage and age factors; wherein, L: low ratio group; M: medium ratio group; H: high ratio group.
图4为本发明一实施例中基于人类表达谱芯片数据的各组双基因标志物按比值的总体生存分析结果图；其中，L：低比值组；H：高比值组。Fig. 4 is a diagram of the overall survival analysis results of each group of digene markers according to the ratio based on the human expression profile chip data in an embodiment of the present invention; wherein, L: low ratio group; H: high ratio group.
具体实施方式Detailed ways
本发明涉及一种用于肌层浸润性膀胱癌诊断和/或生存预后预测的生物标记物，其特征在于，所述生物标记物选自GAS6、PDGFC、DDR2、PDGFRA、FN1、PPARG中的至少一种，更优选为双基因生物标记物GAS6/PPARG、PDGFC/PPARG、DDR2/PPARG、PDGFRA/PPARG和FN1/PPARG中的至少一种。本发明还涉及一种上述生物标记物作为作为肌层浸润性膀胱癌诊断标志物和/生存预后预测标记物的应用。The present invention relates to a biomarker for the diagnosis and/or survival prognosis prediction of muscle invasive bladder cancer, characterized in that the biomarker is selected from at least one of GAS6, PDGFC, DDR2, PDGFRA, FN1, and PPARG One, more preferably at least one of the dual gene biomarkers GAS6/PPARG, PDGFC/PPARG, DDR2/PPARG, PDGFRA/PPARG and FN1/PPARG. The present invention also relates to the application of the above-mentioned biomarker as a diagnostic marker and/or a predictive marker for survival and prognosis of muscle-invasive bladder cancer.
下面结合附图和实施例，对本发明的具体实施方式作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。The specific implementation manners of the present invention will be further described below in conjunction with the drawings and examples. The following examples are only used to illustrate the technical solution of the present invention more clearly, but not to limit the protection scope of the present invention.
实施例1Example 1
本实施例为以405例肌层浸润性膀胱癌的RNA-Seq数据为例，采用双基因生物标记物GAS6/PPARG、PDGFC/PPARG、DDR2/PPARG、PDGFRA/PPARG和FN1/PPARG在预测膀胱癌生存预后中应用，其具体如下：In this example, taking the RNA-Seq data of 405 cases of muscle-invasive bladder cancer as an example, the dual-gene biomarkers GAS6/PPARG, PDGFC/PPARG, DDR2/PPARG, PDGFRA/PPARG and FN1/PPARG were used in the prediction of bladder cancer The application in survival prognosis is as follows:
肿瘤标本的转录组数据和病人总体生存数据下载自The Cancer Genome Atlas(TCGA)数据库(https://portal.gdc.cancer.gov)，数据类型为FPKM(fragments perkilobase of transcript permillion fragments mapped)值。The transcriptome data and patient overall survival data of tumor specimens were downloaded from The Cancer Genome Atlas (TCGA) database (https://portal.gdc.cancer.gov), and the data type was FPKM (fragments perkilobase of transcript permillion fragments mapped) values.
从中提取GAS6、PDGFC、DDR2、PDGFRA、FN1和PPARG的表达值。Spearman相关性分析结果如图1所示，可见GAS6、PDGFC、DDR2、PDGFRA、FN1的表达值均与PPARG的表达值呈负相关。Expression values of GAS6, PDGFC, DDR2, PDGFRA, FN1 and PPARG were extracted from them. The Spearman correlation analysis results are shown in Figure 1. It can be seen that the expression values of GAS6, PDGFC, DDR2, PDGFRA, and FN1 were all negatively correlated with the expression values of PPARG.
针对每组标记物，按基因表达比值，按三位数将病人分成三组，低比值组、中比值组和高比值组，各组标志物比值的分组阈值如表1所示。For each group of markers, patients were divided into three groups according to the ratio of gene expression and three digits, low ratio group, middle ratio group and high ratio group, and the grouping thresholds of marker ratios in each group are shown in Table 1.
表1各细标志物比值的分细阈值Table 1 Subdivision thresholds of each fine marker ratio
对三组病人的总体生存进行生存分析(Kaplan-Meier分析，log-rank检验)，其分析结果如图2所示，可见低比值组的总体生存显著优于其他两组。Survival analysis (Kaplan-Meier analysis, log-rank test) was performed on the overall survival of the three groups of patients, and the analysis results are shown in Figure 2. It can be seen that the overall survival of the low ratio group was significantly better than that of the other two groups.
为确认该组标记物为独立于肿瘤分期和病人年龄之外的独立预测因素，纳入分期和年龄因素进行Cox回归分析，使用SPSS软件按Cox回归分析标准流程操作，其结果如图3所示，其确认各组标志物比值可作为独立预后预测因子。In order to confirm that this group of markers is an independent predictive factor independent of tumor stage and patient age, the stage and age factors were included in Cox regression analysis, and SPSS software was used to operate according to the standard process of Cox regression analysis. The results are shown in Figure 3. It confirmed that the ratio of markers in each group can be used as an independent prognostic predictor.
此外，采用经四分位数标准化的FPKM值，分析结果与上述一致，可见该比值不需要进行样本间标准化处理，可直接比较。In addition, using the quartile-standardized FPKM value, the analysis results are consistent with the above, which shows that the ratio does not need to be standardized between samples and can be directly compared.
实施例2Example 2
本实施例为以73例肌层浸润性膀胱癌的人类表达谱芯片数据为例，采用双基因生物标记物GAS6/PPARG、PDGFC/PPARG、DDR2/PPARG、PDGFRA/PPARG和FN1/PPARG在预测膀胱癌生存预后中应用，其具体如下：In this example, the human expression profiling chip data of 73 cases of muscle-invasive bladder cancer were taken as an example, and the dual-gene biomarkers GAS6/PPARG, PDGFC/PPARG, DDR2/PPARG, PDGFRA/PPARG and FN1/PPARG were used to predict bladder cancer. The application in the prognosis of cancer survival is as follows:
肿瘤标本的转录组数据和病人总体生存数据下载自GEO数据库(登录号GSE48277)，数据类型为人类表达谱芯片数据。The transcriptome data and patient overall survival data of tumor specimens were downloaded from the GEO database (accession number GSE48277), and the data type was human expression profiling microarray data.
与实施例1类似，从中提取PDGFC、DDR2、FN1和PPARG基因的表达值，分别计算每个样本中PDGFC、DDR2、FN1基因与PPARG基因的表达比值。根据比值分布，按中位数分成两组，即高比值组和低比值组。对两组病人的总体生存进行生存分析(Kaplan-Meier分析，log-rank检验)，其结果如图4所示，可见低比值组病人的总体生存显著优于高比值组(PDGFC/PPARG：p<0.01；DDR2/PPARG：p<0.01；FN1/PPARG：p＝0.018)Similar to Example 1, the expression values of PDGFC, DDR2, FN1 and PPARG genes were extracted therefrom, and the expression ratios of PDGFC, DDR2, FN1 genes and PPARG genes in each sample were calculated respectively. According to the ratio distribution, the patients were divided into two groups according to the median, namely the high ratio group and the low ratio group. Carry out survival analysis (Kaplan-Meier analysis, log-rank test) to the overall survival of two groups of patients, its result is shown in Figure 4, it can be seen that the overall survival of low ratio group patient is significantly better than high ratio group (PDGFC/PPARG:p <0.01; DDR2/PPARG: p<0.01; FN1/PPARG: p=0.018)
由上述实施例可知，本发明发现五对均与PPARG有关的生物标志物，即GAS6/PPARG、PDGFC/PPARG、DDR2/PPARG、PDGFRA/PPARG和FN1/PPARG，GAS6、PDGFC、DDR2、PDGFRA和FN1在肿瘤中的表达与PPARG的表达均呈负相关，与PPARG的表达比值可作为分别作为独立的预后指标，采用的指标为两种标志物的表达比值，样本间可直接比较，无需标准化处理，其在肿瘤组织中的表达特征均具有预测肌层浸润性膀胱癌生存预后的价值。As can be seen from the above examples, the present invention found five pairs of biomarkers related to PPARG, namely GAS6/PPARG, PDGFC/PPARG, DDR2/PPARG, PDGFRA/PPARG and FN1/PPARG, GAS6, PDGFC, DDR2, PDGFRA and FN1 The expression in tumors is negatively correlated with the expression of PPARG, and the expression ratio of PPARG and PPARG can be used as independent prognostic indicators. The index used is the expression ratio of the two markers, which can be directly compared between samples without standardization. Its expression characteristics in tumor tissue have the value of predicting the survival and prognosis of muscle-invasive bladder cancer.
以上对本发明的具体实施例进行了详细描述，但其只作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。The specific embodiments of the present invention have been described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, equivalent changes and modifications made without departing from the spirit and scope of the present invention shall fall within the scope of the present invention.
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| CN101027412A (en) * | 2004-07-23 | 2007-08-29 | 环太平洋生物技术有限公司 | Urine markers for detection of bladder cancer |
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